There is now unequivocal evidence that immune responses are modulated by opioids. Most acute and subacute drug administration paradigms result in immunosuppression. There have been few studies examining the effects of chronic drug administration on immune function and even fewer published reports of effects of withdrawal on the immune system. Since intravenous drug abusers frequently go through periods of highs followed by periods of partial or full withdrawal, studies of alterations in immune competence during abstinence are of significant import. In preliminary studies, we have examined the effect of abrupt or precipitated withdrawal (AW or PW) from morphine administered by slow-release pellet on the capacity of mouse spleen cells to mount an ex vivo antibody response. We observed profound alterations in immune function in both withdrawal paradigms. At 3 hr after PW, but not AW, there was immunopotentiation. By 24 hr after initiation of either withdrawal paradigm, mice were >60 percent immunosuppressed, and in AW, suppression was 70 percent at 48 hr, with >50 percent suppression still evident at 144 hr. It is proposed to investigate these two interesting models of robust immune modulation resulting from the two abstinence syndromes. Specifically, we will use AW and PW to: 1) determine the effect of withdrawal on function on various immune cell subsets; 2) assess the effect of withdrawal on resistance to Salmonella, Listeria, and pneumococcal infection; 3) determine which type of opioid receptor mediates alterations in immune function during AW and PW; and 4) investigate the role of pro-inflammatory cytokines nitric oxide, and/or the HPA axis in mediating immunosuppression following withdrawal. These studies should elucidate the mechanisms by which withdrawal alters immune function and determine if immunosuppression leads to increased susceptibility to infection. Investigation of the effects of withdrawal on immune system function has practical and theoretical implications. Alterations in immune status during the abstinence syndrome may provide a heightened sensitivity to infection or reactivation of latent infection, such as HIV or tuberculosis. Dissection of the mechanisms and pathways by which opioids interface with the immune system during withdrawal should elucidate fundamental interconnections between the neural and immune systems.